1. Field of the Invention
The present invention is directed to central nervous system pharmaceutically active compounds having both aryl-substituted piperazine and aminotetralin moieties, 5 or 7 membered cycloaliphatic ring homologues thereof, or open chain analogues thereof; and to their pharmacological use. These hybrid compounds exhibit high activity at various dopamine and serotonin receptor subtypes. Certain of the compounds exhibit high differential selectivity between D2 and D3 receptor subtypes.
2. Background Art
The dopamine receptors of the brain have proven fertile targets for pharmacological treatment of numerous central nervous system (“CNS”) disorders, including psychotic disorders such as schizophrenia and neurodegenerative disorders such as Parkinson's disease.8 
In the last decade and a half, advances have been made in development of drugs specific for dopamine receptor subtypes, and in the development of novel pharmaceutically active compounds for their characterization.1-3 In addition, in 1990, a new dopamine subtype receptor now known as the D3 receptor was discovered and subsequently cloned from rat complimentary DNA libraries using probes derived from the D2 receptor subtype.4,5 This new D3 receptor subtype belongs to the short form of D2 receptor subtype, and bears close resemblance to the latter.5,6,7 
Therapies involving D2-specific drugs often are associated with side effects like EPS, Tardive dyskinesia, believed to originate from blockage of D2 receptors in the striatal region of the brain.9 Studies probing the location of D3 receptors have shown that the distribution of the latter is different from the distribution of D2 receptors. In situ hybridization studies showed a lack of adequate presence in the caudate putamen area of the striatal section, and a dominant presence in the nucleus accumbens area.10 These different distribution patterns render the D3 receptors unique targets for drug development. D3-specific antagonists and agonists are expected to have numerous applications in treatment of psychotic disorders and neurodegenerative diseases without the undesirable side effects associated with pharmacology of the D2 receptor.1,12,13 Recent studies have shown that D3 specific compounds may also have therapeutic use in treatment of cocaine8 addiction.14,15,16 Efforts have thus been made to develop D3 specific drug candidates.
For example, 2-aminotetralins have been regarded as potent and selective agonists for D2 receptors.17-20 However, 7-OH-DPAT and PD 128907, both aminotetralins, have shown preferential activity at the D3 receptor.21 Several other aminotetralin-related derivatives were also found to have such preferential selectivity.22 Aryl piperazines have also been demonstrated to have activity toward the D2 and D3 receptors,23,24 and some of these were found to have both high affinity and selectivity for the D3 receptor.26 One such compound is GR103691,25 containing a N-(methoxyphenyl)piperidine moiety linked to a 4′-acetyldiphenyl moiety through an N-alkyl-N-urethane linking group. A series of 8-hydroxy-2-aminotetralins bearing benzamide moieties have also been shown to have selective affinity for the D3 receptor,27-28 and a thiaza heterocyclic analog was shown to have high affinity and selectivity for this receptor subtype.28 
It would be desirable to provide additional pharmaceutically active compounds which exhibit high levels of CNS activity, for example, with respect to the dopaminergic receptors as well as the serotoninergic receptors. It would be further desirable to provide drug candidates which exhibit high activity with respect to the D3 receptor subtype, and in particular to provide drug candidates which exhibit high selectivity between the D2 and D3 subtypes.